Bone graft containment system

ABSTRACT

The present invention relates to methods for bioresorbable and biodegradable casings having both micropores and macropores for providing shape, structure and containment to different bone grafting materials. Kits and methods of use are also described.

FIELD OF THE INVENTION

The present disclosure generally relates to fillable collagen containersfor use in bone grafting.

BACKGROUND

Artificial or synthetic bone can be used to repair damaged areas wherenatural regeneration may not be feasible or practical. The ability toincorporate new bone growth through osteoconductivity andosteoinductivity are important factors in artificial bone materials.Osteoconductivity is the ability to serve as a scaffold for new bonegrowth while osteoinductivity refers to the ability of graft material toinduce de novo bone growth with biomimetic substances, such as bonemorphogenetic proteins.

Recent advances in tissue engineering have produced materials such ascalcium phosphates that possess both osteoconductive and osteoinductiveproperties, thereby, providing a suitable bone grafting material.Calcium phosphates may include hydroxyapatite (HA) or beta-tricalciumphosphate (βTCP) or biphasic calcium phosphate (a combination of HA andβTCP).

Artificial or synthetic bone, as well as demineralized bone is mostcommonly, and advantageously, used in particulate form as powders orgranules. The particulate nature radically increases the availablesurface area once implanted, improving osteoinductivity. The preferredparticulate nature of graft materials, however, poses a problem whentrying to form larger prostheses for implantation, such as in spinalfusion procedures. The use of putties attempts to address handlingissues with particulate DBM but often require a significant (about 60%in some cases) amount of carrier which dilutes the amount of DBM andtherefore reduces its effectiveness.

Commercially available mesh pouches such as Ballast from SeaSpineHoldings Corporation (Carlsbad, Calif.) and Magnifuse from Medtronic plc(Ireland) have been designed to provide containment and shape toparticulate bone grafting material without relying on putties with largeamounts of carrier. Such pouches also allowing access for bodily fluidsand osteogenic cells to the grafting material therein. Such designsattempt to retain the surface area advantages of particulate graftingmaterials while allowing for containment and shaping for specificprostheses and procedures. However, the materials and specifics used inthe existing designs have their own shortcomings and leave room forimprovement.

SUMMARY

The present invention provides bioresorbable casings having bothmicropores and macropores suitable for containing a variety ofbone-grafting materials while allowing osteogenic cells and bodilyfluids to pass through. In preferred embodiments, the casing may beconstructed of collagen providing advantages over existing mesh pouchesconstructed from absorbable polymers such as polyglycolide (PGA) or poly(lactic-co-glycolic)acid (PLGA) in that the degraded material does notrequire clearance from the body. The casings may be filled withbone-grafting particles such as bioceramics, demineralized bone matrix(DBM), or combinations thereof in any form including fibers, granules,paste, powder, chips, strips, and sponge. The DBM can be obtained fromcortical or cancellous bone. In certain embodiments, the bioceramicsparticles may include HA, tricalcium phosphate, monetite, brushite, ormono-calcium phosphate monohydrate (MCPM). Additional fill materials mayinclude bioglass, collagen-ceramic mixtures, cell based products,autografts, and growth factor containing products.

As noted, the presence of both micropores and macropores differentiatethe present casing from existing products. Those pores may be randomlydistributed or may be localized in specific patterns based on intendeduse and orientation of the implanted casing. Pores may be generatedthrough molding or may be generated after molding through mechanical orthermal techniques such as laser perforation. The casing may comprisenanopores.

Casings may be provided closed and pre-filled with grafting material,ready for implantation. Alternatively, the casing may be provided withan opening. The open casing may be pre-filled with some amount ofgrafting material or may be empty ready for filling by a technician ormedical professional in advance of implantation or as part of theimplantation process. Open casings may remain open or may be closedthrough the use of sutures, adhesives, heat, chemical treatment,pressure, folded or other means before implantation. Sutures may also bemade of collagen. In certain embodiments, by providing an open casing toa surgeon, fresh autologous bone or other cells may be obtained from thepatient and added to the casing at the time of implantation.

Casings may be molded or otherwise formed in a tube shape of desiredsize or may be formed from one or more strips of a material such ascollagen. For example, a strip of collagen mesh may be folded overitself and the folded sides sutured or otherwise joined together to forma pouch.

The adaptability of the casings described herein allows them to beprepared in almost any shape and size for a variety of applications.Casings can be sized and shaped to repair patient-specific injuries ordefects as modeled from radiographic or other patient imaging. Casingcan be provided in standard shapes and sizes for procedures such asspinal fusion (e.g., placement in the posterolateral gutter) across twoor more vertebrae.

To facilitate application-specific implantation, casing of the inventionmay be provided in implantable device kits. Kits may include one or moreof a holder for receiving and positioning a casing for fill, a fillmaterial, a rigid or semi-rigid fill tube to insert into the casing tofacilitate filling, and a plunger to aid in loading the casing withfill. Means for closing the casing after filling such as a suturematerial may also be included.

The casing may be collagen or other materials as described herein. Afill tube can be sized to fit snugly into an opening in the casing toprovide a stable path for fill material to be inserted. The fill tubemay be in two or more portions which may be assembled by inserting oneinto another. The end of the fill tube that is not inserted into thecasing may have a larger cross-sectional profile than the inserted endproviding a funnel shape to facilitate filling. In various embodiments,the funnel portion may be separable from the inserted portion of thefill tube.

The holder may comprise a body sized and shaped similarly to the casingsuch that the casing can be placed in and positioned by the body. Theholder may fully enclose the casing apart from an opening that isaligned with the casing's open end when the casing is positioned in thebody. The holder may comprise two or more pieces including, for example,a lid so that the casing can be placed in the body before the lid isjoined to enclose the casing within the holder. The lid can then beremoved to facilitate removal of the casing after filling. The fill tubemay be shaped and sized to fit snugly within the inlet of the holder.

As noted above, the fill material may comprise any known bone-graftingparticles including DBM from cancellous or cortical bone and bioceramicmaterials. In certain embodiments, fill material may include calciumphosphate materials including biphasic calcium phosphate materials withan osteoinductivity-boosting needle-like or nanorod-like surfacemorphology using hydrothermal and/or chemical processes includingexposure to peroxides (e.g., hydrogen peroxide). Other bioceramic fillmaterials may include monetite, brushite, or MCPM. Additional fillmaterials may include bioglass, collagen-ceramic mixtures, cell basedproducts, autografts, and growth factor containing products.

Aspects of the invention include an implantable bone graft devicecomprising a bioresorbable casing comprising both micropores andmacropores. The bioresorbable casing may comprise collagen. The collagencasing can contain demineralized bone matrix (DBM) in one or moreformats selected from the group consisting of fibers, granules, paste,powder, chips, strips, and sponge. The DBM may be processed from one ormore of the group consisting of cortical and cancellous bone. Thecollagen casing can contain bioceramics in one or more formats selectedfrom the group consisting of fibers, granules, paste, powder, chips,strips, and sponge with or without DBM. In certain embodiments, thebioceramics particles may include HA, tricalcium phosphate, monetite,brushite, or mono-calcium phosphate monohydrate (MCPM). Additional fillmaterials may include bioglass, collagen-ceramic mixtures, cell basedproducts, autografts, and growth factor containing products.

In various embodiments, the implantable device may include nanopores.The micropores, the macropores, and/or the nanopores may be patterned orrandom and may be generated through molding or through variousmechanical or thermal techniques.

The bioresorbable casing can be closed or may comprise an opening forfilling the casing. The bioresorbable casing can be formed by one ormore strips of collagen joined together with sutures. The sutures maycomprise a bioabsorbable material such as polyglycolic acid, polylacticacid, poly(lactic-co-glycolic acid). In some embodiments, sutures maycomprise collagen or any known resorbable or non-resorbable polymer. Incertain embodiments, the bioresorbable casing may be formed from asingle strip of folded collagen. The bioresorbable casing may be moldedin a single piece. The casing may be sized and configured for placementin an anatomical structure of a spine such as in a posterolateral gutterfor spinal fusion.

In certain aspects, a bone grafting method is provided that may compriseimplanting at a target site an implantable device comprising abioresorbable casing comprising both micropores and macropores andfilled with a fill material comprising one or more of the groupconsisting of demineralized bone matrix (DBM) and bioceramics. Prior toimplanting methods of the invention may include providing an implantabledevice comprising an open-ended bioresorbable casing comprising bothmicropores and macropores, filling the open-ended bioresorbable casingwith one or more of the group consisting of demineralized bone matrix(DBM) and bioceramics, and closing the open end of the filledbioresorbable casing. The closing step can include suturing the open endof the filled bioresorbable casing at the time of surgery.

Aspects of the invention can include an implantable device kitcomprising a holder. The holder may include a body configured forreceiving an open-ended bioresorbable casing and sized to accommodatethe open-ended bioresorbable casing when filled and an inlet alignedwith the body and sized to allow the open-ended bioresorbable casing topass through the inlet and into the body.

The body may enclose the bioresorbable casing on all sides apart fromthe inlet. The holder can further include a removable lid that uponremoval, providing access to the body for insertion and removal of theopen-ended bioresorbable casing. Kits may include a fill tube having adistal end having a cross-sectional profile sized to fit within theopen-ended bioresorbable casing and the inlet. The fill tube can includea proximal end having a larger cross-sectional profile than the distalend. The fill tube may have two or more detachably coupled segments.

In certain embodiments, the inlet of the holder and the distal end ofthe fill tube may be sized such that the distal end of the fill tube canbe inserted into the inlet. The inlet of the holder and the distal endof the fill tube can be sized such that the fill tube's outer surfaceforms a seal with an inner surface of the inlet. Kits may include aplunger sized to fit within the fill tube and operable to force a fillmaterial through the fill tube and into the open-ended bioresorbablecasing. The open-ended bioresorbable casing and the fill material may beincluded in kits of the invention.

In certain aspects, methods of the invention may include making animplantable device by providing a kit as described above with a holdercomprising a body configured for receiving an open-ended bioresorbablecasing and sized to accommodate the open-ended bioresorbable casing whenfilled and an inlet aligned with the body and sized to allow theopen-ended bioresorbable casing to pass through the inlet and into thebody; a fill tube having a distal end having a cross-sectional profilesized to fit within the open-ended bioresorbable casing and the inlet;and a plunger sized to fit within the fill tube. Methods may includecoupling an open-ended bioresorbable casing to the fill tube; insertingthe open-ended bioresorbable casing through the inlet and into the bodyof the holder such the fill tube and open-ended bioresorbable casingbecome held by the holder; and inserting, via the plunger, a fillmaterial through the fill tube and into the open-ended bioresorbablecasing to produce a filled open-ended bioresorbable casing.

In certain embodiments, methods may include removing the filledopen-opened ended bioresorbable casing from the holder and uncouplingthe fill tube from the filled open-opened ended bioresorbable casing.Methods can comprise closing the filled open-ended bioresorbable casing.The body may enclose the bioresorbable casing on all sides apart fromthe inlet. The holder may further comprise a removable lid that uponremoval, providing access to the body for insertion and removal of theopen-ended bioresorbable casing. The fill tube can include a distal endhaving a cross-sectional profile sized to fit within the open-endedbioresorbable casing and the inlet. The fill tube can comprise aproximal end having a larger cross-sectional profile than the distalend.

In certain embodiments, the fill tube may include two or more detachablycoupled segments. The inlet of the holder and the distal end of the filltube may be sized such that the distal end of the fill tube can beinserted into the inlet. The inlet of the holder and the distal end ofthe fill tube can be sized such that an outer surface of the fill tubeforms a seal with an inner surface of the inlet.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows an open-ended bioresorbable casing according to certainembodiments.

FIG. 2 shows an exemplary closed bioresorbable casing.

FIG. 3 shows an exemplary open-ended bioresorbable casing with a filltube inserted therein.

FIG. 4 shows an exemplary two-piece fill tube.

FIG. 5 shows an exemplary assembled fill tube.

FIG. 6 shows an exemplary plunger.

FIG. 7 shows an exemplary open-ended bioresorbable casing with a filltube and plunger inserted therein.

FIG. 8 shows an exemplary holder.

FIG. 9 shows an open-ended bioresorbable casing in a body of anexemplary holder.

FIG. 10 shows an open-ended bioresorbable casing enclosed in anexemplary holder.

FIG. 11 shows an exemplary kit of the invention.

FIG. 12 shows an exemplary collagen strip.

DETAILED DESCRIPTION

Systems and methods of the invention relate to bioresorbable casings forproviding containment and shape to bone graft particles. Such casingscan be preferentially made of collagen or other bio-compatible and/ornatural materials. They may be formed of a mesh comprising micro, macro,and/or nanopores. The pores should be sized based on the graft materialcontained therein to prevent the material from escaping and whileallowing osteogenic cells and other biological fluids and materials topass through, providing access to the graft material. Casings may beprovided pre-filled, closed, and ready for use or may be provided opento be filled by a user before use. The open casing may be provided aspart of a kit along with fill material and means for filling and closingthe casing. Methods of preparing and using casings of the invention arealso described herein.

FIGS. 1 and 2 show exemplary bioresorbable casings 101 of the invention.The casing 101 may be made of synthetic materials such as polyesters,polyamides, or polyolefins. Preferred synthetic materials includebiodegradable polymers such as polyglycolide (PGA) andpoly(lactic-co-glycolic acid) (PLGA). In preferred embodiments, thecasing is made of a natural material such as collagen.

Casings preferably have both micropores and macropores. Macroporesgenerally refer to pores between 100 μm to 1000 μm. Micropores generallyrefer to pores less than about 1 μm to 100 μm and, in certainembodiments, between about 1 μm and about 10 μm. In certain embodiments,the casing material may comprise nanopores, generally referring to pores1 μm or smaller.

Any of the above pores may be distributed randomly or patterned acrossthe casing's surface. The pores may be distributed in a pattern based onthe application of the final implant. For example, the macropores may beconcentrated based on the anatomical location of the casing 101 onceimplanted to provide better access to osteogenic cells, fluids, or otherbiological material. Micro and macropores may be randomly distributed orpatterned based on other considerations. FIG. 11 shows an exemplarycollagen strip for use in preparing a casing having an exemplary patternof pores across the surface of the material.

Pores may be formed via molding of the casing material wherein the sizeand distribution of the pores are dictated by the surface features ofthe mold. Casing materials may comprise solid sheets in which pores arecreated via known mechanical, chemical, or thermal processes. In certainembodiments, laser processing is used to form the desired size andpattern of pores in the casing material. In some embodiments, pores maybe punched into the casing.

Casings 101 may be formed into the final desired size and shape throughany known technique including injection or other molding techniques.Casings 101 are preferably prepared with a cavity therein to receive andcontain the graft material. In initial preparation, an opening 105should left by which the graft material can be inserted into the casing101.

The open end 105 may be closed after filling either at a remotemanufacturing site or by a user such as a surgeon or other medicalprofessional before implantation using sutures 203 (FIG. 2). Sutures maybe any biocompatible material including the natural and syntheticmaterials used to form the casing 101. In preferred embodiments, thesutures 203 comprise PGA or PLGA or collagen. Sutures may also includenon-resorbable materials such as polypropylene and polyethylene. Othersealing methods are contemplated including adhesives, heat, andpressure, depending upon the nature of the casing material and intendeduse.

In certain embodiments, the casing 101 may be prepared from one or moresheets of the porous casing material. For example a tube-shaped casing101 may be prepared from two sheets of collagen or other material bylaying the sheets together and suturing or otherwise sealing the sides103 and bottom 107 to form a casing 101 with an opening 105 throughwhich to add graft material. In some embodiments, a single sheet ofporous material may be folded along an edge to form the bottom 107 ofthe casing 101 and then sutured or otherwise joined along the sides 103to create the open-ended casing 101.

Casings 101 can be prepared and used in any size and shape depending onthe intended application. Casing are contemplated for use in medicalprocedures such as orthopedic surgery and maxillofacial procedures. Incertain embodiments, casings of the invention may be sized and shapedfor use in spinal fusion procedures. For example casings and implantsmade therefrom may be configured for placement in a posterolateralgutter for spinal fusion. They may be offered in various sizes dependingon the number and position of the vertebrae to be fused and based on theage and/or size of the patient.

Methods of the invention can include obtaining a casing and optionallyfilling with a graft material if it is not prefilled. Filling maycomprise the use of kit components as described below including one ormore of a holder, a casing, a fill material, a plunger, and a fill tube.A user may then close the casing if it was not prefilled using themethods described above. Methods can include then implanting the filledcasing to repair a bone defect, treat a traumatic injury, perform aspinal fusion, or any other osteogenic treatment calling for a graftprosthesis. Fill material such as those described below, including DBMand/or bioceramics may be obtained in dry form and can be wetted priorto filling. The bioceramics particles may include, for example, HA,tricalcium phosphate, monetite, brushite, or mono-calcium phosphatemonohydrate (MCPM). Additional fill materials may include bioglass,collagen-ceramic mixtures, cell based products, autografts, and growthfactor containing products.

In certain embodiments, bioresorbable casing may be provided in kitform. Kits may include one or more of a casing, a fill material, aholder, a fill tube, and a plunger to facilitate filling of the casingby a user. Additional materials such as syringes and fluids for wettingand preparing fill material and/or the casing may also be included.

An exemplary kit is shown in FIG. 11. The kit includes a holder 801, acasing 101, and a fill tube 301, all shown assembled ready for filling.A plunger 601 is included as well as fill material 1101 shown in a dishfor wetting and preparation as well as a syringe 1103 of fluid forwetting and preparing the fill material 1101.

A fill tube 301 is depicted in FIGS. 3-5. The fill tube 301 should haveat least one end sized to fit within the opening 105 of the casing 101.The tube 301 comprises a lumen through which fill material may be passedinto the casing 101 through the opening 105. The casing material maygenerally offer little material support such that maintaining theopening 105 during filling is difficult. The fill tube 301 can be rigidenough to then maintain the opening 105 for filling. The outer surfaceof the fill tube 301 is preferably sized to fit snugly within theopening 105 and the inner lumen of the fill tube 301 is preferably sizedto allow the passage of fill material therethrough and into the casing101. The outer surface and lumen of the fill tube 301 may be enlarged atthe end not inserted into the opening 105 to ease loading of material.For example, the fill tube 301 may include a funnel 303 at one endproviding a large opening for material to be added followed by a gradualreduction in cross-sectional profile to fit within the casing 101. Thefill tube 301 may comprise multiple parts to ease in packaging or toprovide different funnel 303 options. For example, the fill tube 301 maybe made up of two components including a casing insertion portion 307and a funnel portion 305 which can be assembled prior to filling. Funnelportions 305 of different sizes may be selected based on the fillmaterial.

Fill tubes 301 may be made of any known material including, for example,metal, glass, plastic, and composite materials. In certain embodiments,kits may include a plunger 601 for aiding in casing filling as shown inFIG. 6. The plunger 601 is sized to fit within the lumen of the filltube as sized at the end inserted into the casing 101. The plunger 601may have a single size and shape or may have a smaller handle portion603 and a larger plunging portion 605 to provide a large cross-sectionalarea for forcing fill material into the casing 101.

The plunger 601 preferably has a cross-sectional profile sized justsmaller than the lumen of the fill tube 301 and the opening 105 in thecasing 101 so that fill material cannot readily pass between the insideof the fill tube 301 lumen and the edges of the plunger 601. Fillingaction using the plunger 601 to force fill material through a fill tube301 into the opening 105 of a casing 101 is shown in FIG. 7. The plungermay include features such as serrations or openings in the plungingportion 605 to physically process the fill material during insertionincluding separating granules and avoiding clumping.

Kits may include a holder 801 for supporting and positioning a casing101 for fill. An exemplary holder 801 is shown in FIG. 8. The holder 801can comprise a body 803 sized to accept the casing 101 and align theopening 105 of the casing 101 with an inlet 805 in the body 803 of theholder 801. As noted above with respect to the fill tube 301, the casingmaterial has little rigidity and, therefore filling the casing 101 canbe difficult, even with the use of the fill tube 301. The holder 801 canwork alone or in conjunction with the fill tube 301 to support theoutside of the casing 101 during fill. The holder 801, like the filltube 301, and the plunger 601 may be made out of any known materialincluding, for example, metal, glass, plastic, and composite materials.The holder 801 can be operable to fully enclose the casing 101 onlyproviding access to the opening 105 of the casing 101 through an inlet805 in the holder 801. Accordingly, the holder can assist in maintainingsterility of the casing 101 and minimizing the potential for damagethrough repeated handling of the casing 101 directly.

A casing 101 inserted into the body 803 of a holder 801 is depicted inFIG. 9. The body 803 and the casing 101 are similarly sized and shapedto aid in positioning of the casing opening 105 and the holder inlet805. The holder inlet 805 may also be sized and shaped along with thefill tube 301 such that the fill tube can be passed through the inlet805 into the casing 101 within the body 803. The components can be sizedsuch that the outer surface of the fill tube 301 contacts the inneredges of the inlet 805 and may even form a seal, protecting the outsideof the casing 101 such that the lumen of the fill tube 301 provides theonly access and point of exposure to the casing 101.

In order to facilitate casing 101 placement in and retrieval from thebody 803 of the holder 801, the holder may comprise multiple componentsincluding a lid 1003 as shown in FIG. 10. At least a portion of the body803 may be formed in a base 1005 of the holder 801 such that the casing101 can be positioned therein. The fill tube 301 may be inserted intothe opening 105 of the casing 101 before or after the casing 101 isplaced in the body 803. Once positioned, the lid 1003 or other componentof the holder 801 may then be coupled to the base 1005 to form thecomplete, enclosed body 803 and inlet 805 of the holder 801 with thecasing inside. Once filled, the lid 1003 may be removed and the filledcasing 101 can be taken from the body 803, closed, and implanted.

In various embodiments, casing disclosed herein may be pre-filled with abone-grafting material. Preferably the material is provided inparticulate form to provide increased surface area for infiltration byhost cells and osteogenesis. Materials may include bone material whichmay be obtained from the patient before or during the implantationprocedure. In certain embodiments, DBM may be used to fill the casing.DBM is bone that has had the inorganic mineral removed, leaving behindthe organic matrix. Removal of the bone mineral exposes morebiologically active bone morphogenetic proteins which aid in bone andcartilage formation. DBM is more biologically active than standard bonegrafts but the mechanical properties of the bone are lost. Accordingly,casings of the invention are particularly useful in containing DBM andproviding the mechanical support and shape desired for particular bonegraft prostheses. Any combination of graft materials may be provided inthe form of fibers, granules, paste, powder, chips, strips, sponge, orany other available particle type and any combination of these particletypes.

In various embodiments, fill material may comprise metals, like titaniumor tantalum, polymers like polylactides, hydrogel-based materials, orbioceramics. Bioceramics may include biphasic calcium phosphate whichmay be processed to produce osteoinductive surface morphologies asdescribed below. Additional osteoinductive fill materials as well asprosthesis applications are described in U.S. Pat. Nos. 9,364,583;4,430,760; and 9,801,978, incorporated by reference herein. Fillmaterial may include bioglass, collagen-ceramic mixtures, as well ascell based products and growth factor containing products. See V.Krishnan and T. Lakshmi, 2013, Bioglass: A novel biocompatibleinnovation, J Adv Pharm Technol Res. 4(2): 78-83. Example of materialsand agents which may be added to a fill material in a casing of theinvention include, for example, osteogenic or chondrogenic proteins orpeptides; DBM powder; collagen, insoluble collagen derivatives, etc.,and soluble solids and/or liquids dissolved therein; anti-AIDSsubstances; anti-cancer substances; antimicrobials and/or antibioticssuch as erythromycin, bacitracin, neomycin, penicillin, polymycin B,tetracyclines, biomycin, chloromycetin, and streptomycins, cefazolin,ampicillin, azactam, tobramycin, clindamycin and gentamycin, etc.;immunosuppressants; anti-viral substances such as substances effectiveagainst hepatitis; enzyme inhibitors; hormones; neurotoxins; opioids;hypnotics; anti-histamines; lubricants; tranquilizers; anti-convulsants;muscle relaxants and anti-Parkinson substances; anti-spasmodics andmuscle contractants including channel blockers; miotics andanti-cholinergics; anti-glaucoma compounds; anti-parasite and/oranti-protozoal compounds; modulators of cell-extracellular matrixinteractions including cell growth inhibitors and antiadhesionmolecules; vasodilating agents; inhibitors of DNA, RNA, or proteinsynthesis; anti-hypertensives; analgesics; anti-pyretics; steroidal andnon-steroidal anti-inflammatory agents; anti-angiogenic factors;angiogenic factors and polymeric carriers containing such factors;anti-secretory factors; anticoagulants and/or antithrombotic agents;local anesthetics; ophthalmics; prostaglandins; anti-depressants;anti-psychotic substances; anti-emetics; imaging agents;biocidal/biostatic sugars such as dextran, glucose, etc.; amino acids;peptides; vitamins; inorganic elements; co-factors for proteinsynthesis; endocrine tissue or tissue fragments; synthesizers; enzymessuch as alkaline phosphatase, collagenase, peptidases, oxidases, etc.;polymer cell scaffolds with parenchymal cells; collagen lattices;antigenic agents; cytoskeletal agents; cartilage fragments; living cellssuch as chondrocytes, bone marrow cells, mesenchymal stem cells; naturalextracts; genetically engineered living cells or otherwise modifiedliving cells; expanded or cultured cells; DNA delivered by plasmid,viral vectors, or other member; tissue transplants; autogenous tissuessuch as blood, serum, soft tissue, bone marrow, etc.; bioadhesives; bonemorphogenic proteins (BMPs); osteoinductive factor (IFO); fibronectin(FN); endothelial cell growth factor (ECGF); vascular endothelial growthfactor (VEGF); cementum attachment extracts (CAE); ketanserin; humangrowth hormone (HGH); animal growth hormones; epidermal growth factor(EGF); interleukins, e.g., interleukin-1 (IL-1), interleukin-2 (IL-2);human alpha thrombin; transforming growth factor (TGF-beta);insulin-like growth factors (IGF-1, IGF-2); parathyroid hormone (PTH);platelet derived growth factors (PDGF); fibroblast growth factors (FGF,BFGF, etc.); periodontal ligament chemotactic factor (PDLGF); enamelmatrix proteins; growth and differentiation factors (GDF); hedgehogfamily of proteins; protein receptor molecules; small peptides derivedfrom growth factors above; bone promoters; cytokines; somatotropin; bonedigesters; antitumor agents; cellular attractants and attachment agents;immuno-suppressants; permeation enhancers, e.g., fatty acid esters suchas laureate, myristate and stearate monoesters of polyethylene glycol,enamine derivatives, alpha-keto aldehydes, etc.; and nucleic acids.

Fill materials may include biphasic calcium phosphate with modifiedsurface morphologies prepared using hydrothermal and/or chemicaltreatment such as those described, for example, in U.S. patentapplication Ser. No. 16/828,583.

INCORPORATION BY REFERENCE

References and citations to other documents, such as patents, patentapplications, patent publications, journals, books, papers, webcontents, have been made throughout this disclosure. All such documentsare hereby incorporated herein by reference in their entirety for allpurposes.

EQUIVALENTS

Various modifications of the invention and many further embodimentsthereof, in addition to those shown and described herein, will becomeapparent to those skilled in the art from the full contents of thisdocument, including references to the scientific and patent literaturecited herein. The subject matter herein contains important information,exemplification and guidance that can be adapted to the practice of thisinvention in its various embodiments and equivalents thereof.

What is claimed is:
 1. An implantable bone graft device comprising abioresorbable casing comprising a cavity for receiving and containing afill material and a surface having both micropores and macropores,wherein the macropores are created in a sheet of bioresorbable materialby mechanical, chemical, or thermal process and patterned and sized toprevent the fill material within the cavity from escaping therethroughwhile allowing osteogenic cells to pass through.
 2. The implantabledevice of claim 1 wherein the bioresorbable casing comprises collagen.3. The implantable device of claim 2 wherein the collagen casingcontains demineralized bone matrix (DBM) in one or more formats selectedfrom the group consisting of fibers, granules, paste, powder, chips,strips, and sponge.
 4. The implantable device of claim 3 wherein the DBMis processed from one or more of the group consisting of cortical andcancellous bone.
 5. The implantable device of claim 2 wherein thecollagen casing contains bioceramics in one or more formats selectedfrom the group consisting of fibers, granules, paste, powder, chips,strips, and sponge.
 6. The implantable device of claim 2 wherein thecollagen casing contains demineralized bone matrix (DBM) andbioceramics.
 7. The implantable device of claim 1 wherein the microporesare random.
 8. The implantable device of claim 1 wherein the macroporesare generated through molding.
 9. The implantable device of claim 1wherein the macropores are generated through mechanical or thermaltechniques.
 10. The implantable device of claim 1 wherein thebioresorbable casing is closed.
 11. The implantable device of claim 1wherein the bioresorbable casing comprises an opening for filling thecasing.
 12. The implantable device of claim 2 wherein the bioresorbablecasing is formed by one or more strips of collagen joined together withsutures.
 13. The implantable device of claim 12 wherein the suturescomprise a bioabsorbable material selected from the group consisting ofpolyglycolic acid, polylactic acid, and poly(lactic-co-glycolic acid).14. The implantable device of claim 12 wherein the bioresorbable casingis formed from a single strip of folded collagen.
 15. The implantabledevice of claim 1 wherein the bioresorbable casing is molded in a singlepiece.
 16. The implantable device of claim 1 sized and configured forplacement in an anatomical structure of a spine.
 17. The implantabledevice of claim 16 sized and configured for placement in aposterolateral gutter for spinal fusion.
 18. A bone grafting methodcomprising: implanting at a target site an implantable device comprisinga bioresorbable casing comprising: a surface having both micropores andmacropores created in a sheet of bioresorbable material by mechanical,chemical, or thermal process; and a cavity filled with a fill materialcomprising one or more of the group consisting of demineralized bonematrix (DBM) and bioceramics, wherein the macropores are patterned andsized to prevent the fill material from escaping therethrough whileallowing osteogenic cells to pass through.
 19. The bone grafting methodof claim 18, wherein prior to implanting, the method further comprises:providing an implantable device comprising an open-ended bioresorbablecasing comprising both micropores and macropores; filling the open-endedbioresorbable casing with one or more of the group consisting ofdemineralized bone matrix (DBM) and bioceramics; and closing the openend of the filled bioresorbable casing.
 20. The method of claim 19wherein the closing step comprises suturing the open end of the filledbioresorbable casing.
 21. The bone grafting method of claim 18 whereinthe target site comprises an anatomical structure of a spine.
 22. Themethod of claim 18 wherein the DBM matrix is in one or more formatsselected from the group consisting of fibers, granules, paste, powder,chips, strips, and sponge.
 23. The method of claim 18 wherein the DBMmatrix is processed from one or more of the group consisting of corticaland cancellous bone.
 24. The method of claim 18 wherein the bioceramicscomprise one or more formats selected from the group consisting offibers, granules, paste, powder, chips, strips, and sponge.